Inhibition of STAT3 activity delays obesity-induced thyroid carcinogenesis in a mouse model. Compelling epidemiologic studies indicate that obesity is a risk factor for many human cancers, including thyroid cancer. In recent decades, the incidence of thyroid cancer has dramatically increased along with a marked rise in obesity prevalence. We previously demonstrated that a high fat diet (HFD) effectively induced the obese phenotype in a mouse model of thyroid cancer (TRbetaPV/PVPten+/- mice). Moreover, HFD activates the STAT3 signal pathway to promote more aggressive tumor phenotypes. The aim of the present study was to evaluate the effect of S3I-201, a specific inhibitor of STAT3 activity, on HFD-induced aggressive cancer progression in the mouse model of thyroid cancer. Wild type and TRbetaPV/PVPten+/- mice were treated with HFD together with S3I-201 or vehicle-only as controls. We assessed the effects of S3I-201 on HFD-induced thyroid cancer progression, the leptin-JAK2-STAT3 signaling pathway, and key regulators of epithelial-mesenchymal transition. S3I-201 effectively inhibited HFD-induced aberrant activation of STAT3 and its downstream targets to markedly inhibit thyroid tumor growth and to prolong survival. Decreased protein levels of cyclins D1 and B1, cyclin dependent kinase (CDK) 4, CDK 6, and phosphorylated retinoblastoma TRbetaPV/PVPten+/- mice. Reduced occurrence of vascular invasion and blocking of anaplasia and lung metastasis in thyroid tumors of S3I-201-treated TRbetaPV/PVPten+/- mice were mediated via decreased expression of vimentin and matrix metalloproteinases, two key effectors of epithelial-mesenchymal transition. The present findings suggest that inhibition of the STAT3 activity would be a novel treatment strategy for obesity-induced thyroid cancer. Metformin blocks progression of obesity-activated thyroid cancer in a mouse model. We previously demonstrated that a high fat diet (HFD) effectively induces the obese phenotype in a mouse model of aggressive follicular thyroid cancer (TRbetaPV/PVPten+/- mice). We showed that HFD promotes cancer progression through aberrant activation of the leptin-JAK2-STAT3 signaling pathway. HFD-promoted thyroid cancer progression allowed us to test other molecular targets for therapeutic opportunity for obesity-induced thyroid cancer. Metformin is a widely used drug to treat patients with type II diabetes. It has been shown to reduce incidences of neoplastic diseases and cancer mortality in type II diabetes patients. The present study aimed to test whether metformin could be a therapeutic for obesity-activated thyroid cancer. TRbetaPV/PVPten+/- mice were fed HFD together with metformin or vehicle-only, as controls, for 20 weeks. While HFD- TRbetaPV/PVPten+/- mice had shorter survival than LFD-treated mice, metformin had no effects on the survival of HFD- TRbetaPV/PVPten+/- mice. Remarkably, metformin markedly decreased occurrence of capsular invasion and completely blocked vascular invasion and anaplasia in HFD- TRbetaPV/PVPten+/- mice without affecting thyroid tumor growth. The impeded cancer progression was due to the inhibitory effect of metformin on STAT3-ERK-vimentin and fibronectin-integrin signaling to decrease tumor cell invasion and de-differentiation. The present studies provide additional molecular evidence to support the link between obesity and thyroid cancer risk. Importantly, our findings suggest that metformin could be used as an adjuvant in combination with antiproliferative modalities to improve the outcome of patients with obesity-activated thyroid cancer. SAHA-induced loss of the tumor suppressor Pten gene promotes thyroid carcinogenesis in a mouse model. Thyroid cancer is on the rise. Novel approaches are needed to improve the outcome of patients with recurrent and advanced metastatic thyroid cancers. FDA approval of suberoylanilide hydroxamic acid (SAHA; vorinostat), an inhibitor of histone deacetylase, for the treatment of hematologic malignancies led to the clinical trials of vorinostat for advanced thyroid cancer. However, patients were resistant to vorinostat treatment. To understand the molecular basis of the resistance, we tested the efficacy of SAHA in two mouse models of metastatic follicular thyroid cancer: ThrbPV/PV and Th TRbetaPV/PVPten+/- mice. In both, thyroid cancer is driven by over-activation of PI3K-AKT signaling. But the latter exhibit more aggressive cancer progression due to haplodeficiency of the tumor suppressor, the Pten gene. SAHA had no effects on thyroid cancer progression in ThrbPV/PV mice, indicative of resistance to SAHA. Unexpectedly, thyroid cancer progressed in SAHA-treated TRbetaPV/PVPten+/- mice with accelerated occurrence of vascular invasion, anaplastic foci, and lung metastasis. Molecular analyses showed further activated PI3K-AKT in thyroid tumors of SAHA-treated TRbetaPV/PVPten+/- mice, resulting in the activated effectors, p-Rb, CDK6, p21Cip1, p-cSrc, ezrin and matrix metalloproteinases to increase proliferation and invasion of tumor cells. Single molecule DNA analysis indicated that the wild-type allele of the Pten gene was progressively lost while carcinogenesis progressed in SAHA-treated TRbetaPV/PVPten+/- mice. Thus, the present studies have uncovered a novel mechanism by which SAHA-induced loss of the tumor suppressor Pten to promote thyroid cancer progression. Effectors downstream of the Pten loss-induced signaling may be potential targets to overcome resistance of thyroid cancer to SAHA.